In this application, we evaluate an internalizing pathway to substance use disorders (SUDs) and consider the etiology of Negative Affect SUDs, a potential phenotype of SUDs identifiable by comorbidity with disorders involving negative affect (i.e., depression and anxiety). We conduct an integrative (secondary) analysis (refined in our prior project period) involving the simultaneous analysis of three nationally prominent longitudinal studies of children of alcoholic parents and matched controls that collectively span the first four decades of life (ages 2 through 38). Understanding developmental pathways leading to SUDs is critical in efforts to design and implement effective intervention and treatment programs for youth. Although behavioral indicators of risk for adolescent substance involvement appear as early as 2-5 years of age, few theories about developmental pathways to SUDs consider risk processes that begin in the preschool years. Moreover, few studies are capable of evaluating theories about these developmental pathways. Longitudinal studies that span the first four decades of life, when SUDs emerge, peak and begin to decline, are rare. Available cohort- or population-based studies often yield too few cases to disentangle different pathways for SUDs. Thus, long-term, longitudinal studies of high-risk populations, such as children of alcoholic parents, are invaluable for articulating developmental pathways to SUDs. Using this method, we pursue five specific aims: (1) to define and test an internalizing pathway to SUDs and to evaluate whether evidence supports heterotypic continuity (i.e., different developmental expressions of a single underlying trait) of Negative Affect SUDs over time, (2) to examine the developmentally-varying unique, mediated and interactive effects of internalizing and externalizing processes as predictors of substance involvement and Negative Affect SUDs across the first four decades of life, (3) to examine gender, parental depressive alcoholism, and contextual factors as important moderators of progression along an internalizing pathway toward Negative Affect SUDs as a function of developmental timing, (4) to examine whether the predictive utility of an internalizing model differs over various substances used in isolation (i.e., alcohol, tobacco, marijuana, stimulant and depressant drug) or in combination with one another, and (5) to develop methods for integrative analysis, to utilize these methods to test Aims 1-4, and to disseminate these methods to other applied researchers. PUBLIC HEALTH RELEVANCE: Our application tests an internalizing pathway to substance use disorder over the first four decades of life. Studies of such early emerging but persistent pathways are rare but critical to efforts to design and implement effective intervention and treatment programs for youth.